rs139718656

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004586.3(RPS6KA3):c.1989C>T(p.Asp663Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000935 in 1,208,438 control chromosomes in the GnomAD database, including 6 homozygotes. There are 297 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 3 hom., 149 hem., cov: 23)

Exomes 𝑓: 0.00052 ( 3 hom. 148 hem. )

Consequence

RPS6KA3
NM_004586.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.246

Publications

0 publications found

Variant links:

Genes affected

RPS6KA3 (HGNC:10432): (ribosomal protein S6 kinase A3) This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains 2 non-identical kinase catalytic domains and phosphorylates various substrates, including members of the mitogen-activated kinase (MAPK) signalling pathway. The activity of this protein has been implicated in controlling cell growth and differentiation. Mutations in this gene have been associated with Coffin-Lowry syndrome (CLS). [provided by RefSeq, Jul 2008]

RPS6KA3 Gene-Disease associations (from GenCC):

Coffin-Lowry syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, ClinGen, G2P
intellectual disability, X-linked 19
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
symptomatic form of Coffin-Lowry syndrome in female carriers
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

RPS6KA3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant X-20156220-G-A is Benign according to our data. Variant chrX-20156220-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.246 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00499 (559/111950) while in subpopulation AFR AF = 0.0176 (540/30743). AF 95% confidence interval is 0.0163. There are 3 homozygotes in GnomAd4. There are 149 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 559 AD,XL gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA3	NM_004586.3 link	c.1989C>T	p.Asp663Asp	synonymous_variant	Exon 21 of 22	ENST00000379565.9	NP_004577.1	P51812A0A384MDW3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KA3	ENST00000379565.9 link	c.1989C>T	p.Asp663Asp	synonymous_variant	Exon 21 of 22	1	NM_004586.3	ENSP00000368884.3		P51812

Frequencies

GnomAD3 genomes

AF:

0.00500

AC:

560

AN:

111895

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00104

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000370

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00331

GnomAD2 exomes

AF:

0.00137

AC:

252

AN:

183474

AF XY:

0.000795

show subpopulations

Gnomad AFR exome

AF:

0.0174

Gnomad AMR exome

AF:

0.000620

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.000442

GnomAD4 exome

AF:

0.000521

AC:

571

AN:

1096488

Hom.:

Cov.:

AF XY:

0.000409

AC XY:

148

AN XY:

361874

show subpopulations

African (AFR)

AF:

0.0174

AC:

459

AN:

26364

American (AMR)

AF:

0.000795

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19375

East Asian (EAS)

AF:

0.00

AC:

AN:

30196

South Asian (SAS)

AF:

0.0000739

AC:

AN:

54110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.000484

AC:

AN:

4129

European-Non Finnish (NFE)

AF:

0.0000250

AC:

AN:

840552

Other (OTH)

AF:

0.00124

AC:

AN:

46026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00499

AC:

559

AN:

111950

Hom.:

Cov.:

AF XY:

0.00436

AC XY:

149

AN XY:

34152

show subpopulations

African (AFR)

AF:

0.0176

AC:

540

AN:

30743

American (AMR)

AF:

0.00104

AC:

AN:

10574

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3569

South Asian (SAS)

AF:

0.000371

AC:

AN:

2693

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6083

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53206

Other (OTH)

AF:

0.00327

AC:

AN:

1529

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00175

Hom.:

Bravo

AF:

0.00580

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Coffin-Lowry syndrome;C0796225:Intellectual disability, X-linked 19

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Aug 05, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Sep 20, 2015

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Feb 06, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

6.9

(source)

DANN

Benign

0.44

PhyloP100

0.25

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=82/18

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over